Synthesis of many pharmaceuticals which contain a hydroxyethylamine isostere, such as the aspartyl protease HIV protease inhibitors, involves an amine opening of an epoxide intermediate. Such pharmaceuticals contain chiral centers that can be introduced in the synthesis of the drug by utilizing a chiral epoxide intermediate. The preparation of such epoxides, including chiral epoxides, may require a multi-step synthesis starting from a L-amino acid such as L-phenylalanine or an amino acid derivative such as an alcohol like phenylalaninol. Historically, such epoxides were prepared by methods that involved reduction of a chloromethylketone intermediate. This can lead to low overall yields. The chloromethylketone was frequently prepared by a process that required the use of the highly toxic and highly explosive diazomethane. Because of the nature of diazomethane, its use generally is not applicable to the large scale (multikilogram) production of either intermediates or final products. Furthermore the overall yield for diastereoselective reduction of chloroketones, especially those used in the preparation of HIV-protease inhibitors, can be low.
An improved process for the preparation of such epoxide intermediates is disclosed in WO 93/23388 and WO 95/14653. The process involves the cold temperature reaction of a halomethyl lithium reagent with an aldehyde intermediate. This process is particularly suited for the preparation of chiral epoxide intermediates but it requires the cooling of large reactors containing large quantities of solvent and reagents. A less convenient and less efficient method of generating a halomethyl lithium reagent from lithium metal for reaction with an alpha-aminoaldehyde compound is disclosed in WO 9617821. The present invention relates to an improvement in this halomethyl organometallic reagent addition to an aldehyde carbonyl method of preparing epoxides. In particular, the invention is directed to the diastereoselective production of chiral epoxides utilizing a continuous flow process wherein a reagent or reagents can be added with or without priming more or less at the same time (more or less simultaneously) in an uninterrupted fashion.
Roberts et al, Science, 248, 358 (1990), Krohn et al, J. Med. Chem. 344, 3340 (1991) and Getman, et al, J. Med. Chem., 346, 288 (1993) have previously reported synthesis of HIV-protease inhibitors containing the hydroxyethylamine, hydroxyethylurea or hydroxyethylsulfonamide isostere which included the opening of an epoxide generated in a multi-step synthesis starting from an amino acid. These methods also contain steps which include diazomethane as a reagent in the synthesis of chloromethylketones and the reduction of amino chloromethyl ketone intermediates to an amino halo-alcohol prior to formation of the epoxide. The overall yields of these syntheses are low. In addition, as noted above the use of toxic and explosive diazomethane prevents such methods from being useful for the commercial or pilot plant production of drugs. Thus, in spite of the prior art's ability to synthesize HIV-protease inhibitors, more efficient, environmentally acceptable and commercially desirable processes are needed.
Tinker et al U.S. Pat. No. 4,268,688 disclose a catalytic asymmetric hydroformylation process for preparing optically active aldehydes from unsaturated olefins. Similarly, Reetz et al U.S. Pat. No. 4,990,669 disclose the formation of optically active alpha amino aldehydes through the reduction of alpha amino carboxylic acids or their esters with lithium aluminum hydride followed by oxidation of the resulting protected beta amino alcohol by dimethyl sulfoxide/oxalyl chloride or chromium trioxide/pyridine. Alternatively, protected alpha amino carboxylic acids or esters thereof can be reduced with diisobutylaluminum hydride to form the protected amino aldehydes.
Reetz et al (Tet. Lett., 30, 5425 (1989) disclose the use of sulfonium and arsonium ylides and their reactions with protected alpha-amino aldehydes to form aminoalkyl epoxides. This method suffers from the use of highly toxic arsonium compounds or the use of combination of sodium hydride and dimethyl sulfoxide which is extremely hazardous on a large scale. Matteson, et. al., Syn. Lett., 1991, 631 reported the addition of chloromethyllithium or bromomethyllithium to achiral or racemic aldehydes.